While devices for administering liquid medicaments to patients have been provided heretofore in a variety of forms, this invention provides a device for the purpose of the type which comprises a housing, a compressible flexible reservoir for receiving the medicament in this housing, a filling valve to enable filling of the reservoir, a passage communicating with the reservoir and of a defined cross section and length so as, at least in part, to control the rate of outflow to the patient and, connected with this passage, a suitable outlet cannula designed to suit the particular application, e.g. a catheter or a needle.
Such devices can also be termed infusion pumps and infusion pumps are utilized in the treatment of patients in a limited number of cases for particular disorders. There are two basic fields of application of such infusion pumps:
In one field, a pharmacological substance can be used to treat a local disorder of a particular organ (e.g. pain). In a second field of application, the infusion pump can be utilized to improve a bodily function which is insufficient (e.g. blood purification) or can be employed to relieve an acute crisis condition.
An example of the latter application is the infusion of an antiarrhythmic pharmaceutical for patients of cardiac disorders resulting from variation in pacemaker activity. Such devices serve primarily to prevent heart failure because the timing of the infusion prevents or interrupts an arrhythmic condition. Such pumps are usually implanted.
Another group of pumps represent the types utilized to replace an insufficiency of certain body fluids of particular organs and which lack represent a pathological condition itself. The replacement of such body fluids falls in the realm of endocrinology.
A particular example in which the failure of an organ can result in a deficiency of supply of a particular liquid requiring the infusion of a substitute, is the failure of the pancreas to produce sufficient insulin, a body fluid which is essential to life.
At the present time, patients suffering from an insulin deficiency are treated mainly by injection of insulin, a therapy which, after several years, can give rise to various organ failures.
A further group of patients may require blood replacement therapy or synthetic blood cleaning.
In many modes of treatment heretofore employed, the fluid required for body treatment hereinafter referred to a a liquid medicament whether it is a replacement fluid, a fluid utilized to provide a blood cleaning or like function of a pharmaceutical used for treatment or relief of a particular symptom, is provided in a storage receptacle and delivered to the body of the patient by a pump unit, the storage receptacle being refilled at intervals.
The application can be oral (resorption of the liquid via the intestinal tract), subcutaneous (resorption via the lymph system) or venous or arterial, i.e. intravenous or intraarterial. Intraperitoneal infusions are today used in treatment only for insulin therapy.
While the present invention has a principal application in the subcutaneous infusion of insulin and may be described hereinafter in this connection, it will be understood that in principle it can be used wherever a constant-rate therapy with an infusion pump from which the liquid medicament is delivered to an organ of the body at a substantially constant flow rate, can be utilized for various purposes including:
(1) to cover the basal requirement, especially when, as is often the case, long action duration insulin is effective;
(2) where peripheral insulin resistance requires application of the normal insulin requirement uniformly over the entire day for a positive therapeutic effect; and
(3) where the treatment is of the so-called type II disorder, where the infusion of insulin is required to cover the prandial (food intake) requirements to permit the pancreas to have a rest function which enables its recovery and thus makes the pancreas better able to perform the normal sensor function and normal insulin supply.
However, it should be understood, as to the invention, that it is in no way limited to the subcutaneous application of insulin. Indeed, it is useful wherever long term injection of a liquid is required or desirable, e.g. for the exact dosing of medicaments for blood purification, for local treatment with antibiotics and for local analgesic therapy. Since the device of the invention can also be implanted, it can eliminate drawbacks of a host of the prior art implanted infusion pumps.
In order to appreciate the various problems which are solved by the device of the invention, it is important to understand some of the requirements for both insulin pumps which are applied on the surface of the body and those which are implanted. Infusion systems which normally mounted on the bed of a patient need not be discussed since they are far more remote from the invention.
The following list defines the biological and technical categories of problems:
(a) life of the pump, e.g. the length of time the pump remains operative without requiring replacement;
(b) reliability and redundancy;
(c) controllability of the pump and the manner (power source) by which it is driven;
(d) biological sensor for automatic control (closed loop) of the infusion;
(e) durability and function of the output cannula;
(f) energy supply; and
(g) safety.
Other criteria such as implantability and price, also play a role.
In practice, the implantation pumps provided at the present time for a constant delivery rate can comprise a flexible insulation container at a superatmospheric pressure with the flow controlled by a throttle or a cross-section-reducing cannula. These all deliver insulin at a rate which is proportional to pressure.
The pressure is supplied, generally with the aid of an intervening membrane by a drive gas (FREON). A drive gas can be used as the energy source for a pump in the manner described, for example, in Europatent publication EP-OS 0128703 for delivering the liquid via a valve which can be controlled by the patient and is external of the patient body.
An interesting concept, which is nevertheless affected with all of the problems of high energy requirements, is found in U.S. Pat. No. 4,505,710 in which the control of a piston is effected by two reciprocal chambers supplied with the drive gas. The piston is shifted by heating the chambers on respective sides thereof electrically so that the higher vapor pressure on the respective side shifts the piston. In this system, the flow throttle is eliminated.
The latter also applies to the system described in Europatent publication EP-OS No. 0091624 which utilizes vapor pressure as an energy source. Here, the vapor transits through a semipermeable membrane which delays passage of the gas.
A superatmospheric pressure also operates the pump described in Europatent publication EP-OS No. 0098893 in the construction between a high pressure gas chamber and the medicament receptacle to a further closed compartment is prevented. A fine control valve of the gas container supplies the intermediate compartment with pressure which then operates upon the flexible medicament.
Other known pump systems (German printed application DE-AS No. 2124062 and U.S. Pat. No. 38,356) deal with further developments of transportational systems.
For example, the Siemens firm of West Germany has developed a miniaturized roller-type peristaltic pump which can be carried easily on the body and controlled by the patient.
An implantable control has also been developed as will be apparent from German Open Application DE-OS No. 3,018,833 and the Europatent application No. 0019814. The function of such implantable dispensers is theoretically advantageous, since it allows the patient to eat at will, but the implantation itself is fraught with difficulty.
For example, the quantity of the liquid infused into the body is dependent upon the elasticity of a silicone rubber tube and it has long been recognized that silicone rubber in the body especially in direct contact with the body tissues, will degenerate. In practice, it has been found that the useful life of such pumps will be from one to a maximum of two years. The pumps are driven by small stepping motors with transmissions and these elements also have a limited reliability in biological milieus. A highly stable system is described in the International application WO-OS No. 8502344. Here a flexible liquid receptacle (i.e. a metal bellows) is compressed by a device which in principal includes a spindle driven by an electric motor. Osmotic forces are also used to compress the elastic medicament receptacle.
Thus, for example, in the German printed application No. 2,201,533 (based upon a U.S. Patent application Ser. No. 106,161) describes various designs involving two flexible receptacles of which a first (medicament receptacle) is compressed by the second osmotically active receptacle.
A common characteristic of the various designs is a rigid outer housing so that the water uptake by the osmotically active material will result in an enlargement of the osmotic receptacle which is thereby confined so that its pressure can be applied to the medicament receptacle.
Among the various designs is a torus-like configuration. However, it can be remarked that the physical principle by which these designs of infusion pumps operate is significantly different from the physical principle under which the invention operates.
An improvement utilizing the osmotic principle is described in U.S. Pat. No. 3,604,417. In this system, the medicament part of the device is separated from the osmotic drive and the latter comprises two shiftable pistons having a defined range of action for the osmotic material.
A further known pump system operates in the form of a membrane pump with intake and discharge valves. Such pumps have long useful lives, but have problems with respect to their size, since liquid controlled valves generally are sizeable because they require a valve seat, a valve member engageable with the seat, a restoring spring acting on the valve member . . . . Another important disadvantage of such valves is their opening and closing characteristics.
If one wishes to pump 1 to 2 .mu.l and for closing a valve several .mu.l is required, this can create a problem. Indeed, when the pump is to deliver a volume with precision and deviations of say 50% (amounting to 1 .mu.l) may result, as in such cases, the pump may be unsatisfactory.
U.S. Pat. Nos. 4,265,241 and 4,260,019 describe similar pumps, the latter representing a further development of a same basal construction.
In this latter pump configuration, the safety aspect has been considered and valve redundancy has been introduced together with a special device for generating a reduced pressure in the liquid receptacle so that upon failure of the valve system there will be no direct danger for the patient.
Because of dimensional considerations with such dispensers, however, there is a limitation on the size of the liquid receptacle which can only work with low-concentration insulin so that a high refilling rate (for example, every two weeks) results. This is not acceptable for most patients.
In U.S. Pat. No. 4,209,014, there is described a system involving a mechanical pressing of an elastic but permeable synthetic resin with the aid of an electromagnetically driven piston. The synthetic resin which does not have a closed structure, for example foam rubber or polyurethane foam, is slightly permeable to pharmaceuticals. If such a synthetic resin is mechanically compressed with the aid of a piston, the flow rate can be significantly increased.
The advantage of simplified construction, however, is associated with disadvantages, for example the compression can increase the quantity delivered only by a factor of three. The throughflow in the noncompressed rate of the synthetic resin requires nonetheless a primary pressure in the liquid vessel. A long operating life cannot be ensured for such purposes, since the long term elasticity of the synthetic resin which is required for an exact metering of material, cannot be ensured. Furthermore, the energy consumption in compression of such elastic materials is relatively large in the device of this patent (greater than 1 watt).
In Austrian Patent No. 378,123, a special configuration of two pistons and two cylinders composed of metal is described. This system has the advantage of long operating life. The device operates by the drawing principal and does not require any conventional valves with valve springs. The features of this construction include the low drawing volume (0.3 to 1.5 .mu.l per cycle), a pump volume determined by the number of pump cycles, and electromagnetic control of the pump.
Finally, mention must be made of the Austrian Pat. No. 360,636 which describes a dispenser and can be said to form the starting point for the present invention. In this case, a sausage-shaped tube of a special synthetic resin material is inflated, because of its special construction with a liquid so that upon emptying, over a predetermined range of elasticity, it is possible to generate a substantially constant pressure versus time characteristic (the term "constant" here permitting in accordance with the teachings of the Patentee a fluctuation of about 10%).
The system of this latter patent has a number of disadvantages including the retention of a high residual volume in the tube following the discharge over the constant rate portion. The design also is intended exclusively for external use. Only a limited number of synthetic materials can be used, since only such materials have the required characteristics. It is also questionable whether the materials used are biocompatible and compatible with the liquids to be dispensed, since many of the medicaments, such as insulin, are highly sensitive.
Since the system is not prestressed and only the linear region of the force dilation curve is usable, there is a further loss in volume deliverable at a constant rate.
Externally driven pumps utilizing the same principles or implantable pumps (piston pumps, roller peristaltic pumps . . . ) are utilized in miniaturized mechanical or spindle-driven form and includes spindle drives for hypodermic syringes and the like. Such pumps can have speed controls. The state of the art also has developed programs for control, for example, a precalculated daily profile for insulin delivery (See W. J. SPENCER, A Review of Programmed Insulin Delivery Systems: IEEE Transactions on Biomedical Engineering, Vol. BME-28 No. 3, March 1981).
Drawbacks and discomforts resulting from such external pumps include:
(a) excessive bulk of the entire pump system and marginal acceptability of them by patients on social grounds;
(b) excessive service costs, especially for programmable pumps which are fraught with optional failures and can introduce the risk of hypoglycemia for the patient;
(c) problems of hygiene in carrying the pumps (e.g. in showering or bathing);
(d) unsatisfactory condition relating to the outlet in cannula, e.g. in the case of injection, needles, an inflammation resulting from long term lying, sensitivity and also, for example dislocation upon tension applied to the catheter;
(e) high price: generally ranging between 30,000 to 50,000 Austrian Schilling corresponding to approximately $2,500.-to $4,000.-.
The following disadvantages characterize gas-driven pumps:
(a) variation of the delivered dose resulting from temperature fluctuations, e.g. in the case of a feverish patient;
(b) a reduced absolute pressure of the drive gas and a consequent alteration in pump volume in dependence upon sea level, causing problems with respect to patients who are flying or in sea travel;
(c) the need for a metal bellows because of detrimental effects of the drive gases;
(d) variation in the pump rate of up to 50% upon emptying of the pump resulting from the intrinsic characteristics of the metal bellows required to separate the liquid and the drive gas.